Hybrid biologic-synthetic bioabsorbable scaffolds

ABSTRACT

A bioprosthetic device is provided for soft tissue attachment, reinforcement, and or reconstruction. The device comprises a naturally occurring extracellular matrix portion and a synthetic portion.

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/567,886, filed May 4, 2004; and U.S. Provisional PatentApplication No. 60/571,766, filed May 17, 2004. Both of theseprovisional patent applications are hereby incorporated by reference.

CROSS REFERENCE

Cross reference is made to copending U.S. patent application Ser. No.10/195,794 entitled “Meniscus Regeneration Device and Method” (AttorneyDocket No. 265280-71141, DEP-745); Ser. No. 10/195,719 entitled “Devicesfrom Naturally Occurring Biologically Derived Materials” (AttorneyDocket No. 265280-71142, DEP-748); Ser. No. 10/195,347 entitled“Cartilage Repair Apparatus and Method” (Attorney Docket No.265280-71143, DEP-749); Ser. No. 10/195,344 entitled “Unitary SurgicalDevice and Method” (Attorney Docket No. DEP-750); Ser. No. 10/195,606entitled “Cartilage Repair and Regeneration Device and Method” (AttorneyDocket No. 265280-71145, DEP-752); Ser. No. 10/195,354 entitled “PorousExtracellular Matrix Scaffold and Method” (Attorney Docket No.265280-71146, DEP-747); Ser. No. 10/195,334 entitled “Cartilage Repairand Regeneration Scaffolds and Method” (Attorney Docket No.265280-71180, DEP-763); and Ser. No. 10/195,633 entitled “PorousDelivery Scaffold and Method” (Attorney Docket No. 265280-71207,DEP-762), each of which is assigned to the same assignee as the presentapplication, each of which was filed on Jul. 15, 2002, and each of whichis hereby incorporated by reference. Cross reference is also made toU.S. patent application Ser. No. 10/172,347 entitled “HybridBiologic-Synthetic Bioabsorbable Scaffolds” which was filed on Jun. 14,2002 and U.S. patent application Ser. No. 10/195,341 entitled “HybridBiologic/Synthetic Porous Extracellular Matrix Scaffolds” which wasfiled on Jul. 15, 2002, both of which are assigned to the same assigneeas the present application, and which are hereby incorporated byreference. Cross reference is also made to U.S. patent application Ser.No. ______, (Attorney Docket No. 265280-77861, DEP5314NP) entitled“Hybrid Biologic-Synthetic Bioabsorbable Scaffolds” which was filedconcurrently herewith, is assigned to the same assignee as the presentapplication, and is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to bioprosthetics and particularly to theuse of bioprosthetics for the repair and replacement of connectivetissue. More particularly, the present invention relates to the use of acomposite bioprosthetic device made up of a synthetic portion andheterologous animal tissue.

BACKGROUND AND SUMMARY OF THE INVENTION

Currently there are multiple patents and publications which describe indetail the characteristics and properties of small intestine submucosa(SIS). See, for example, U.S. Pat. Nos. 4,352,463, 4,902,508, 4,956,179,5,281,422, 5,372,821, 5,445,833, 5,516,533, 5,573,784, 5,641,518,5,645,860, 5,668,288, 5,695,998, 5,711,969, 5,730,933, 5,733,868,5,753,267, 5,755,791, 5,762,966, 5,788,625, 5,866,414, 5,885,619,5,922,028, 6,056,777, and WO 97/37613, incorporated herein by reference.SIS, in various forms, is commercially available from Cook BiotechIncorporated (Bloomington, Ind.). Further, U.S. Pat. No. 4,400,833 toKurland and PCT publication having International Publication Number WO00/16822 provide information related to bioprosthetics and are alsoincorporated herein by reference.

It is also known to use naturally occurring extracellular matrices(ECMs) to provide a scaffold for tissue repair and regeneration. Onesuch ECM is small intestine submucosa (SIS). SIS has been used torepair, support, and stabilize a wide variety of anatomical defects andtraumatic injuries. Commercially-available SIS material is derived fromporcine small intestinal submucosa that remodels the qualities of itshost when implanted in human soft tissues. Further, it is taught thatthe SIS material provides a natural matrix with a three-dimensionalmicrostructure and biochemical composition that facilitates host cellproliferation and supports tissue remodeling. SIS products, such asOasis material and Surgisis material, are commercially available fromCook Biotech, Bloomington, Ind.

An SIS product referred to as RESTORE Orthobiologic Implant is availablefrom DePuy Orthopaedics, Inc. in Warsaw, Indiana. The DePuy product isdescribed for use during rotator cuff surgery, and is provided as aresorbable framework that allows the rotator cuff tendon to regenerateitself. The RESTORE Implant is derived from porcine small intestinesubmucosa that has been cleaned, disinfected, and sterilized. Smallintestine submucosa (SIS) has been described as a naturally-occurringECM composed primarily of collagenous proteins. Other biologicalmolecules, such as growth factors, glycosaminoglycans, etc., have alsobeen identified in SIS. See Hodde et al., Tissue Eng. 2(3): 209-217(1996); Voytik-Harbin et al., J. Cell Biochem., 67:478-491 (1997);McPherson and Badylak, Tissue Eng., 4(1): 75-83 (1998); Hodde et al.,Endothelium, 8(1):11-24 (2001); Hodde and Hiles, Wounds, 13(5): 195-201(2001); Hurst and Bonner, J. Biomater. Sci. Polym. Ed., 12(11) 1267-1279(2001); Hodde et al., Biomaterial, 23(8): 1841-1848 (2002); and Hodde,Tissue Eng., 8(2): 295-308 (2002), all of which are incorporated byreference herein. During seven years of preclinical testing in animals,there were no incidences of infection transmission from the implant tothe host, and the SIS material has not decreased the systemic activityof the immune system. See Allman et al., Transplant, 17(11): 1631-1640(2001); Allman et al., Tissue Eng., 8(1): 53-62 (2002).

While small intestine submucosa is available, other sources of submucosaare known to be effective for tissue remodeling. These sources include,but are not limited to, stomach, bladder, alimentary, respiratory, orgenital submucosa, or liver basement membrane. See, e.g., U.S. Pat. Nos.6,379,710, 6,171,344, 6,099,567, and 5,554,389, hereby incorporated byreference. Further, while SIS is most often porcine derived, it is knownthat these various submucosa materials may be derived from non-porcinesources, including bovine and ovine sources. Additionally, the ECMmaterial may also include partial layers of laminar muscular is mucosa,muscular is mucosoa, lamina propria, stratum compactum and/or othertissue materials depending upon factors such as the source from whichthe ECM material was derived and the delamination procedure.

For the purposes of this invention, it is within the definition of anaturally occurring ECM to clean, delaminate, and/or comminute the ECM,or even to cross-link the collagen fibers within the ECM. It is alsowithin the definition of naturally occurring ECM to fully or partiallyremove one or more sub-components of the naturally occurring ECM.However, it is not within the definition of a naturally occurring ECM toseparate and purify the natural collagen or other components orsub-components of the ECM and reform a matrix material from the purifiednatural collagen or other components or sub-components of the ECM. Whilereference is made to SIS, it is understood that other naturallyoccurring ECMs (e.g., stomach, bladder, alimentary, respiratory, andgenital submucosa, and liver basement membrane), whatever the source(e.g., bovine, porcine, ovine) are within the scope of this disclosure.Thus, in this application, the terms “naturally occurring extracellularmatrix” or “naturally occurring ECM” are intended to refer toextracellular matrix material that has been cleaned, disinfected,sterilized, and optionally cross-linked. The terms “naturally occurringextracellular matrix” and “naturally occurring ECM” are also intended toinclude ECM foam material prepared as described in U.S. PatentApplication No. 60/388,761 entitled “Extracellular Matrix Scaffold andMethod for Making the Same” (Attorney Docket 265280-69963, DEP 702).

There are currently many ways in which various types of tissues such asligaments and tendons, for example, are reinforced and/or reconstructed.Suturing the tom or ruptured ends of the tissue is one method ofattempting to restore function to the injured tissue. Sutures may alsobe reinforced through the use of synthetic non-bioabsorbable orbioabsorbable materials. Autografting, where tissue is taken fromanother site on the patient's body, is another means of soft tissuereconstruction. Yet another means of repair or reconstruction can beachieved through allografting, where tissue from a donor of the samespecies is used. Still another means of repair or reconstruction of softtissue is through xenografting in which tissue from a donor of adifferent species is used.

According to the present invention, a bioprosthetic device for softtissue attachment, reinforcement, and/or reconstruction is provided. Thebioprosthetic device comprises SIS or other ECM formed to include atissue layer, and a synthetic portion coupled to the tissue layer. Thetissue layer may also be dehydrated.

In one embodiment, the SIS portion of the bioprosthetic device includesa top tissue layer of SIS material and a bottom tissue layer of SISmaterial coupled to the top tissue layer. The synthetic portion of thebioprosthetic device includes a row of fibers positioned to lie betweenthe top and bottom tissue layers of the SIS portion. The fibers arepositioned to lie in a spaced-apart coplanar relation to one anotheralong a length, L, of the SIS portion. The fibers are each formed toinclude a length L2, where L2 is longer than L so that an outer endportion of each fiber extends beyond the SIS portion in order to anchorthe bioprosthetic device to the surrounding soft tissue.

Illustratively, in another embodiment, the synthetic reinforcing portionof the bioprosthetic device includes a mesh member formed to define thesame length, L, as the SIS portion, or may include a mesh member havinga body portion coupled to the SIS portion and outer wing members coupledto the body portion and positioned to extend beyond the length, L, and awidth, W, of the SIS portion in order to provide more material foranchoring the bioprosthetic device to the surrounding soft tissue.

The synthetic reinforcing portion of the device enhances the mechanicalintegrity of the construct in one (for fiber reinforcements) or two (forfiber or mesh reinforcements) dimensions. For the repair of tissues suchas meniscal or articular cartilage, or discs, integrity in threedimensions is desirable for the implant to withstand the shear forcesthat will be present after implantation. Thus, in one embodiment of thepresent application, the absorbable synthetic portion of the device isin a three-dimensional form, to provide mechanical strength in threedimensions. The absorbable synthetic may be a fibrous nonwoven constructor a three-dimensional woven mesh, for example.

For the repair of certain other types of tissues such as tendons,ligaments, or fascia, tissue infiltration and repair in three dimensionsis desirable, although three-dimensional enhanced mechanical integrityof the implant is not necessary. Thus, another embodiment of thisinvention is a composite device comprised of an SIS portion and anabsorbable synthetic foam. The absorbable synthetic foam, in oneexample, is made of a biocompatible polymer that has a degradationprofile that exceeds that of the SIS portion of the device. In thiscase, the SIS portion of the device provides the initial suturability ofthe product, and the synthetic foam provides an increased surface areain three dimensions for enhanced tissue infiltration. In a furtherembodiment, that synthetic foam is made of 65/35 polyglycolicacid/polycaprolactone, or 60/40 polylactic acid/polycaprolactone, or a50:50 mix of the two.

The ECM portion of the composite may be provided as a single, hydratedsheet of SIS. Alternatively, the single sheet of SIS is lyophilized(freeze-dried). Such a treatment renders increased porosity to the SISsheet, thereby enhancing it's capacity for allowing tissue ingrowth.Additionally, this SIS portion may comprise multiple sheets of SIS thathave been laminated together by mechanical pressure while hydrated. Thelaminated SIS assembly optionally further physically crosslinked bypartially or fully drying (down to less than 15% moisture content) undervacuum pressure. Alternatively, the laminated SIS assembly islyophilized, instead of being vacuum dried, to increase its porosity. Instill another embodiment, the SIS sheet or laminate is perforated bymechanical means, to create holes ranging, for example, from 1 mm to 1cm. Another embodiment uses woven textiles of single or multi-layer SISstrips that have been optionally vacuum dried or lyophilized, to createmeshes having different-sized openings. The woven mesh SIS optionally isassembled while the SIS is still hydrated and then the whole assemblyvacuum-dried or lyophilized. Such a construct is suturable in the shortterm, and has the advantage of having a very open structure for tissueingrowth over time.

The three-dimensional synthetic portion of the device is illustrativelyprovided in the form of a fibrous nonwoven or foam material. Thesynthetic portion of the device preferably has interconnecting pores orvoids to facilitate the transport of nutrients and/or invasion of cellsinto the scaffold. The interconnected voids range in size, for example,from about 20 to 400 microns, preferably 50 to 250 microns, andconstitute about 70 to 95 percent of the total volume of the construct.The range of the void size in the construct can be manipulated bychanging process steps during construct fabrication. The foam optionallymay be formed around a reinforcing material, for example, a knittedmesh.

The synthetic reinforcing portion of the device is made of a fibrousmatrix made, for example, of threads, yarns, nets, laces, felts, andnonwovens. An illustrated method of combining the bioabsorbable fibrousmaterials, e.g. fibers, to make the fibrous matrix for use in devices ofthe present invention is known to one skilled in the art as the wet layprocess of forming nonwovens. The wet lay method has been described in“Nonwoven Textiles,” by Radko Krcma, Textile Trade Press, Manchester,England, 1967 pages 175-176.

Alternatively, the synthetic reinforcing portion of the device is madeof a three-dimensional mesh or textile. A preferred method of combiningthe bioabsorbable fibrous materials, e.g. fibers, to make the fibrousmatrix for use in devices of the present invention is known to oneskilled in the art as three-dimensional weaving or knitting. Thethree-dimensional weaving/knitting or braiding method has been describedby several groups who have used the constructs for tissue engineeringapplications including Chen et al. in “Collagen Hybridization withPoly(1-Lactic Acid) Braid Promotes Ligament Cell Migration,” Mater. Sci.Eng. C, 17(1-2), 95-99(2001), and Bercovy et al., in “Carbon-PLGAProstheses for Ligament Reconstruction Experimental Basis and Short TermResults in Man,” Clin. Orthop. Relat. Res., (196), 159-68(1985). Such athree-dimensional material can provide both reinforcement andthree-dimensional form.

The synthetic reinforcing portion of the tissue implant of the presentinvention may include textiles with woven, knitted, warped knitted(i.e., lace-like), nonwoven, and braided structures. In an exemplaryembodiment the reinforcing component has a mesh-like structure. However,in any of the above structures, mechanical properties of the materialcan be altered by changing the density or texture of the material. Thefibers used to make the reinforcing component can be for example,monofilaments, yarns, threads, braids, or bundles of fibers. Thesefibers can be made of any biocompatible material, includingbioabsorbable materials such as polylactic acid (PLA), polyglycolic acid(PGA), polycaprolactone (PCL), polydioxanone (PDO), trimethylenecarbonate (TMC), polyvinyl alcohol (PVA), copolymers or blends thereof.In an exemplary embodiment, the fibers that comprise the nonwoven orthree-dimensional mesh are formed of a polylactic acid and polyglycolicacid copolymer at a 95:5 mole ratio.

The ECM and the synthetic three-dimensional portion are provided inlayers. It is understood for the purposes of this invention that theterm “coupled to” describes a relationship wherein a surface of onelayer is in contact with a surface of another layer and the two surfacesare connected through mechanical or chemical means, such as throughlamination, crosslinking, diffusion of the material of one layer intointerstices of the adjacent layer, stitching, and the like. “Sandwichedbetween” describes a relationship wherein a middle layer has a firstsurface in contact with a surface of an adjacent layer, and a secondopposite-facing surface in contact with a surface of a second adjacentlayer. Again, it is understood that the sandwiched layers are connectedthrough mechanical or chemical means. The synthetic reinforcing portionmay be provided as individual fibers or as layers. The syntheticreinforcing portion may be imbedded within a foam layer, providedbetween two other layers that are otherwise coupled together, or mayform a layer that is coupled to one or more adjacent layers.

It is anticipated that the devices of the present invention can becombined with one or more bioactive agents (in addition to those alreadypresent in naturally occurring ECM), one or more biologically-derivedagents or substances, one or more cell types, one or more biologicallubricants, one or more biocompatible inorganic materials, one or morebiocompatible synthetic polymers and one or more biopolymers. Moreover,the devices of the present invention can be combined with devicescontaining such materials.

“Bioactive agents” include one or more of the following: chemotacticagents; therapeutic agents (e.g. antibiotics, steroidal andnon-steroidal analgesics and anti-inflammatories, anti-rejection agentssuch as immunosuppressants and anti-cancer drugs); various proteins(e.g. short chain peptides, bone morphogenic proteins, glycoprotein andlipoprotein); cell attachment mediators; biologically active ligands;integrin binding sequence; ligands; various growth and/ordifferentiation agents (e.g. epidermal growth factor, IGF-I, IGF-II,TGF-β I-III, growth and differentiation factors, vascular endothelialgrowth factors, fibroblast growth factors, platelet derived growthfactors, insulin derived growth factor and transforming growth factors,parathyroid hormone, parathyroid hormone related peptide, bFGF; TGF_(β)superfamily factors; BMP-2; BMP-4; BMP-6; BMP-12; sonic hedgehog; GDF5;GDF6; GDF8; PDGF); small molecules that affect the upregulation ofspecific growth factors; tenascin-C; hyaluronic acid; chondroitinsulfate; fibronectin; decorin; thromboelastin; thrombin-derivedpeptides; heparin-binding domains; heparin; heparan sulfate; DNAfragments and DNA plasmids. If other such substances have therapeuticvalue in the orthopaedic field, it is anticipated that at least some ofthese substances will have use in the present invention, and suchsubstances should be included in the meaning of “bioactive agent” and“bioactive agents” unless expressly limited otherwise.

“Biologically derived agents” include one or more of the following: bone(autograft, allograft, and xenograft) and derivates of bone; cartilage(autograft, allograft, and xenograft), including, for example, meniscaltissue, and derivatives; ligament (autograft, allograft, and xenograft)and derivatives; derivatives of intestinal tissue (autograft, allograft,and xenograft), including for example submucosa; derivatives of stomachtissue (autograft, allograft, and xenograft), including for examplesubmucosa; derivatives of bladder tissue (autograft, allograft, andxenograft), including for example submucosa; derivatives of alimentarytissue (autograft, allograft, and xenograft), including for examplesubmucosa; derivatives of respiratory tissue (autograft, allograft, andxenograft), including for example submucosa; derivatives of genitaltissue (autograft, allograft, and xenograft), including for examplesubmucosa; derivatives of liver tissue (autograft, allograft, andxenograft), including for example liver basement membrane; derivativesof skin tissue; platelet rich plasma (PRP), platelet poor plasma, bonemarrow aspirate, demineralized bone matrix, insulin derived growthfactor, whole blood, fibrin and blood clot. Purified ECM and othercollagen sources are also intended to be included within “biologicallyderived agents.” If other such substances have therapeutic value in theorthopaedic field, it is anticipated that at least some of thesesubstances will have use in the present invention, and such substancesshould be included in the meaning of “biologically-derived agent” and“biologically-derived agents” unless expressly limited otherwise.

“Biologically derived agents” also include bioremodelable collageneoustissue matrices. The expressions “bioremodelable collagenous tissuematrix” and “naturally occurring bioremodelable collageneous tissuematrix” include matrices derived from native tissue selected from thegroup consisting of skin, artery, vein, pericardium, heart valve, duramater, ligament, bone, cartilage, bladder, liver, stomach, fascia andintestine, tendon, whatever the source. Although “naturally occurringbioremodelable collageneous tissue matrix” is intended to refer tomatrix material that has been cleaned, processed, sterilized, andoptionally crosslinked, it is not within the definition of a naturallyoccurring bioremodelable collageneous tissue matrix to purify thenatural fibers and reform a matrix material from purified naturalfibers. The term “bioremodelable collageneous tissue matrices” includes“extracellular matrices” within its definition.

“Cells” include one or more of the following: chondrocytes;fibrochondrocytes; osteocytes; osteoblasts; osteoclasts; synoviocytes;bone marrow cells; mesenchymal cells; stromal cells; stem cells;embryonic stem cells; precursor cells derived from adipose tissue;peripheral blood progenitor cells; stem cells isolated from adulttissue; genetically transformed cells; a combination of chondrocytes andother cells; a combination of osteocytes and other cells; a combinationof synoviocytes and other cells; a combination of bone marrow cells andother cells; a combination of mesenchymal cells and other cells; acombination of stromal cells and other cells; a combination of stemcells and other cells; a combination of embryonic stem cells and othercells; a combination of precursor cells isolated from adult tissue andother cells; a combination of peripheral blood progenitor cells andother cells; a combination of stem cells isolated from adult tissue andother cells; and a combination of genetically transformed cells andother cells. If other cells are found to have therapeutic value in theorthopaedic field, it is anticipated that at least some of these cellswill have use in the present invention, and such cells should beincluded within the meaning of “cell” and “cells” unless expresslylimited otherwise. Illustratively, in one example of embodiments thatare to be seeded with living cells such as chondrocytes, a sterilizedimplant may be subsequently seeded with living cells and packaged in anappropriate medium for the cell type used. For example, a cell culturemedium comprising Dulbecco's Modified Eagles Medium (DMEM) can be usedwith standard additives such as non-essential amino acids, glucose,ascorbic acid, sodium pyrovate, fungicides, antibiotics, etc., inconcentrations deemed appropriate for cell type, shipping conditions,etc.

“Biological lubricants” include: hyaluronic acid and its salts, such assodium hyaluronate; glycosaminoglycans such as dermatan sulfate, heparansulfate, chondroiton sulfate and keratan sulfate; synovial fluid andcomponents of synovial fluid, including mucinous glycoproteins (e.g.lubricin), tribonectins, articular cartilage superficial zone proteins,surface-active phospholipids, lubricating glycoproteins I, II;vitronectin; and rooster comb hyaluronate. “Biological lubricant” isalso intended to include commercial products such as ARTHREASE™ highmolecular weight sodium hyaluronate, available in Europe from DePuyInternational, Ltd. of Leeds, England, and manufactured byBio-Technology General (Israel) Ltd., of Rehovot, Israel; SYNVISC® HylanG-F 20, manufactured by Biomatrix, Inc., of Ridgefield, N.J. anddistributed by Wyeth-Ayerst Pharmaceuticals of Philadelphia, Pa.;HYLAGAN® sodium hyaluronate, available from Sanofi-Synthelabo, Inc., ofNew York, N.Y., manufactured by FIDIA S.p.A., of Padua, Italy; andHEALON® sodium hyaluronate, available from Pharmacia Corporation ofPeapack, N.J. in concentrations of 1%, 1.4% and 2.3% (for opthalmologicuses). If other such substances have therapeutic value in theorthopaedic field, it is anticipated that at least some of thesesubstances will have use in the present invention, and such substancesshould be included in the meaning of “biological lubricant” and“biological lubricants” unless expressly limited otherwise.

“Biocompatible polymers” is intended to include both synthetic polymersand biopolymers (e.g. collagen). Examples of biocompatible polymersinclude: polyesters of [alpha]-hydroxycarboxylic acids, such aspoly(L-lactide) (PLLA) and polyglycolide (PGA); poly-p-dioxanone (PDO);polycaprolactone (PCL); polyvinyl alcohol (PVA); polyethylene oxide(PEO); polymers disclosed in U.S. Pat. Nos. 6,333,029 and 6,355,699; andany other bioresorbable and biocompatible polymer, co-polymer or mixtureof polymers or co-polymers that are utilized in the construction ofprosthetic implants. In addition, as new biocompatible, bioresorbablematerials are developed, it is expected that at least some of them willbe useful materials from which orthopaedic devices may be made. Itshould be understood that the above materials are identified by way ofexample only, and the present invention is not limited to any particularmaterial unless expressly called for in the claims.

“Biocompatible inorganic materials” include materials such ashydroxyapatite, all calcium phosphates, alpha-tricalcium phosphate,beta-tricalcium phosphate, calcium carbonate, barium carbonate, calciumsulfate, barium sulfate, polymorphs of calcium phosphate, sintered andnon-sintered ceramic particles, and combinations of such materials. Ifother such substances have therapeutic value in the orthopaedic field,it is anticipated that at least some of these substances will have usein the present invention, and such substances should be included in themeaning of “biocompatible inorganic material” and “biocompatibleinorganic materials” unless expressly limited otherwise.

It is expected that various combinations of bioactive agents,biologically derived agents, cells, biological lubricants, biocompatibleinorganic materials, biocompatible polymers can be used with the devicesof the present invention.

Thus, in one aspect of this invention a bioprosthetic device is providedcomprising a layer of ECM material having a first surface, and athree-dimensional synthetic portion having a first surface, wherein thefirst surface of the ECM layer is coupled to the first surface of thethree-dimensional synthetic portion. The three-dimensional syntheticportion may be a fibrous material, illustratively selected from thegroup consisting of mesh, textile, and felt. Alternatively, thethree-dimensional synthetic portion may be a synthetic foam.

In another aspect of this invention a prosthetic device is providedcomprising one or more layers of bioremodelable collageneous tissuematrices material coupled to one or more three-dimensional syntheticbodies to provide a three-dimensional composite for tissue attachment,reinforcement, or reconstruction.

In yet another aspect of this invention, a method for making abioprosthetic device is provided, the method comprising the steps ofproviding a layer of ECM material having a first surface, placing apolymer solution in contact the first surface of the ECM material tomake an assembly, wherein the polymer is selected to form a foam uponlyophilization, and lyophilizing the assembly.

Additional features of the present invention will become apparent tothose skilled in the art upon consideration of the following descriptionof preferred embodiments of the invention exemplifying the best mode ofcarrying out the invention as presently perceived.

BRIEF DESCRIPTION OF THE DRAWINGS

The detailed description particularly refers to the accompanying figuresin which:

FIG. 1 is a perspective view showing a composite bioprosthetic device ofthe present invention formed to include a small intestinal submucosa(SIS) portion and a synthetic portion and showing the SIS portionincluding a top tissue layer of SIS material and a bottom tissue layerof SIS material and further showing the synthetic portion including arow of four fibers positioned to lie in coplanar relation to each otherbetween the top and bottom tissue layers of the SIS portion andpositioned to run longitudinally along a length of the SIS portion andextend beyond a first and second end of the SIS portion in order toanchor the bioprosthetic device to surrounding soft tissue;

FIG. 2 is a perspective view similar to FIG. 1 showing an SIS portion ofanother bioprosthetic device of the present invention being formed toinclude a top layer, a bottom layer, and two middle layers positioned tolie between the top and the bottom layers and a synthetic device beingformed to include three rows of four fibers so that each row ispositioned to lie between each of the adjacent tissue layers of the SISportion so that each fiber is positioned to run longitudinally along alength, L, of the SIS portion;

FIG. 3 is a sectional view taken along line 3-3 of FIG. 2 showing thetop, bottom, and middle tissue layers of the SIS portion and alsoshowing the three rows of fibers of the synthetic portion of thebioprosthetic device;

FIG. 4 is a perspective view showing an SIS portion of yet anotherbioprosthetic device of the present invention being formed to includefour tissue layers, similar to FIG. 2, and also showing a syntheticportion of the bioprosthetic device including a first row of multiplefibers positioned to lie between two tissue layers of the SIS portionalong a length, L, of the SIS portion and a second row of multiplefibers positioned to lie between two other tissue layers of the SISportion along a width, W, of the SIS portion;

FIG. 5 is an exploded perspective view of another bioprosthetic deviceof the present invention showing an SIS portion of the prosthetic deviceincluding top, bottom, and middle tissue layers and showing a syntheticportion including a first and a second mesh member positioned to liebetween the top and middle tissue layers of and the middle and bottomtissue layers of the SIS portion, respectively;

FIG. 6 is a sectional view of the bioprosthetic device of FIG. 5 showingfirst and second mesh members “sandwiched” between the tissue layers ofthe SIS portion of the device;

FIG. 7 is a perspective view showing an SIS portion of anotherbioprosthetic device being formed to include a top and a bottom tissuelayer and further showing a synthetic portion being formed to include amesh member having a body portion positioned to lie between the top andbottom tissue layers and outer wing portions provided for anchoring thedevice to surrounding soft tissue;

FIG. 8 is a perspective view showing an SIS portion of yet anotherbioprosthetic device being formed to include a circularly shaped top andbottom tissue layers each having a diameter, D1, and further showing asynthetic portion of the device being formed to include a circular meshmember positioned to lie between the top and bottom tissue layers andhaving a diameter, D2, which is larger than D1 so that an outer rimportion of the mesh member is formed to extend beyond the top and bottomtissue layers for anchoring the bioprosthetic device to the host tissueduring surgery;

FIG. 9 is a sectional view of a bioprosthetic device similar to thebioprosthetic device of FIG. 5, having two SIS layers, a reinforcingmesh material between the SIS layers, and a reinforced three-dimensionalfoam portion adjacent one of the SIS layers;

FIG. 10 is sectional view of another bioprosthetic device, wherein theSIS layer is sandwiched between two foam layers;

FIG. 11 is sectional view of another bioprosthetic device, wherein afoam layer is sandwiched between SIS layers;

FIG. 12 is a sectional view of another bioprosthetic device, wherein athree-dimensional synthetic layer is sandwiched between two SIS layers;and

FIG. 13 is a perspective view showing an SIS portion for use in anotherbioprosthetic device, wherein the SIS layer is made from weaving stripsof SIS.

DETAILED DESCRIPTION OF THE DRAWINGS

A composite bioprosthetic device 10, as shown in FIG. 1, is provided forthe purposes of soft tissue attachment, reinforcement, and/orreconstruction. Bioprosthetic device 10 includes a small intestinalsubmucosa (SIS) portion 12 and a synthetic portion 14. SIS portion 12 isprovided to be absorbed into the body and replaced by host tissue. SISportion 12 acts as a scaffold for tissue ingrowth and remodeling.Synthetic portion 14 of bioprosthetic device 10 provides additionalinitial mechanical strength to bioprosthetic device 10. Because device10 includes SIS portion 12 and synthetic portion 14, bioprostheticdevice 10 is provided with a differential in biodegradation andbioremodeling rates. Synthetic portion 14, for example, can beconfigured to degrade at a slower rate than SIS portion 12. Further,synthetic portion 14 may act as an anchor to couple bioprosthetic device10 to the surrounding soft tissue (not shown) during surgery.Alternatively, the SIS portion may be sutured to couple thebioprosthetic device to the surrounding tissue.

SIS portion 12 of bioprosthetic device 10, as shown in FIG. 1, includesa top tissue layer 16 and a bottom tissue layer 18 coupled to top tissuelayer 16 mechanically or through a dehydration process. Although top andbottom tissue layers 16, 18 are provided in bioprosthetic device 10shown in FIG. 1, it is within the scope of this disclosure, as will bedescribed in more detail later, to include SIS portions 12 having anynumber of tissue layers. It is also included within the scope of thisdisclosure to provide perforated tissue layers or any other physicalconfiguration of SIS. See FIGS. 2-4, for example. Further, it is withinthe scope of this disclosure to define top and bottom tissue layers 16,18 as including multiple tissue layers each. In preferred embodiments,for example, top and bottom tissue layers 16, 18 each include three tofour layers of SIS tissue. SIS portion 12 further includes a first end20, a second end 22 spaced-apart from first end 20, and sides 24 coupledto and positioned to lie between first and second ends 20, 22. A length,L, is defined as the distance between first end 20 and second end 22 anda width, W, is defined as the distance between sides 24.

Synthetic portion 14 of bioprosthetic device 10 includes row 26 of fourfibers 28, as shown in FIG. 1. It is within the scope of the disclosureto define fibers to include fibers or any fibrous material. Fibers 28are positioned to lie along length L between top and bottom tissuelayers 16, 18 and are further positioned to lie in coplanar relation toone another. When making bioprosthetic device 10, fibers 28 of syntheticportion 14 are placed between top and bottom tissue layers 16, 18 priorto dehydration. Although row 26 of four fibers 28 is provided inbioprosthetic device 10 shown in FIG. 1, it is within the scope of thisdisclosure to include synthetic portions 14 formed to include any numberof rows 26 having any number of fibers 28. It is further within thescope of this disclosure to include fibers 28 made from bioabsorbableand non-bioabsorbable materials. For example, it is within the scope ofthis disclosure to include fibers 28 made from polylactic acid (PLA) orpolyglycolic (PGA) acid, a combination of the two, Panacryl™ absorbablesuture (Ethicon, Inc, Somerville, N.J.), other bioabsorbable materials,nylon, polyethylene, Kevlar™, Dacron™, PTFE, carbon fiber, or othernon-bioabsorbable materials.

As shown in FIG. 1, each fiber 28 of bioprosthetic device 10 includestwo outer end portions 30 a middle portion 32 coupled to and positionedto lie between outer end portions 30. Middle portion 32 is positioned tolie between top tissue layer 16 and bottom tissue layer 18 of SISportion 12. Middle portion 32 of fibers 28 helps to provide strengthalong length, L, of bioprosthetic device 10. One or more outer endportions 30 of fibers 28 can be used for anchoring bioprosthetic device10 to surrounding soft tissue (not shown). The combination of SISportion 12 and fibers 28 further provide bioprosthetic device 10 withdifferential biodegradation rates. For example, fibers 28 of syntheticportion 14 can be made to be non-bioabsorbable or can be made withmaterial which absorbs into the body at a slower rate than SIS portion12. Uses for bioprosthetic device 10 shown in FIG. 1 include, but arenot limited to, ligament or tendon repair.

An alternate bioprosthetic device 110 is shown in FIGS. 2 and 3.Bioprosthetic device 110 include an alternate SIS portion 112 of havingtop tissue layer 16, bottom tissue layer 18, and two middle tissuelayers 115. Top, bottom, and middle tissue layers 16, 18, 115 includeone or more layers of SIS tissue each. SIS portion 112, similar to SISportion 12, also includes a first end 20, a second end 22 spaced-apartfrom first end 20, and sides 24. Bioprosthetic device 110 furtherincludes an alternate synthetic portion 114 having three rows 26 of fourfibers 28. One row 26 is positioned to lie between top tissue layer 16and one of the middle tissue layers 115. Another row 26 is positioned tolie between the two middle tissue layers 115, and the final row 26 offibers 28 is positioned to lie between another one of the middle tissuelayers 115 and bottom tissue layer 16, as shown in FIG. 3. Fibers 28 ofbioprosthetic device 110, similar to fibers 28 of bioprosthetic device10, are positioned to lie along length, L, of SIS portion 112.

Although fibers 28 of bioprosthetic devices 10, 110 are positioned tolie along length, L, of each respective SIS portion 12, 112, it iswithin the scope of this disclosure to include a synthetic portion 214of an alternate bioprosthetic device 210, as shown in FIG. 4, havingmulti-directional fibers 28 positioned to lie along a length, L, of anSIS portion 212 and along width, W, of SIS portion 212. Syntheticportion 214 of bioprosthetic device 210 includes a first row 226 havingseventeen fibers 28 positioned to lie along length, L, of SIS portion212. Synthetic portion 214 further includes a second row 227 havingeighteen fibers 28 positioned to lie along width, W, of SIS portion 212so that the fibers 28 of first row 226 and second row 227 are positionedto lie orthogonally with respect to each other. Although rows 226 and227 are positioned to lie in orthogonal relation to one another, it iswithin the scope of this disclosure to include synthetic portion 214having first and second rows 226 and 227 which lie at any angularrelation to one another. It is also within the scope of this disclosureto include rows 226 and 227 each having any number of fibers 28.

Similar to bioprosthetic device 110 shown in FIG. 2, bioprostheticdevice 210 includes a top tissue layer 216, a bottom tissue layer 218,and two middle tissue layers 215, positioned to lie between top andbottom tissue layers 216, 218. As mentioned before, top, bottom, andmiddle tissue layers 216, 218, 215 are each formed to include one ormore layers of SIS tissue. Although SIS portion 212 of bioprostheticdevice 210 is shown to include four tissue layers, it is within thescope of the disclosure to include bioprosthetic device 210 having anynumber of tissue layers. As shown in FIG. 4, first row 226 is positionedto lie between top tissue layer 216 and one of the two middle tissuelayers 215 positioned to lie adjacent to top tissue layer 216. Secondrow 227 is positioned to lie between the other middle tissue layer 215and bottom tissue layer 218. It is within the scope of this disclosure,however, to include rows 226, 227 positioned to lie between any tissuelayer of device 210.

Yet another bioprosthetic device 310 is shown in FIGS. 5 and 6.Bioprosthetic device 310 is similar to devices, 10, 110, and 210 andincludes an SIS portion 312 having a top tissue layer 316, a bottomtissue layer 318, and a middle tissue layer 315 positioned to liebetween top and bottom tissue layers 316, 318. Top, bottom, and middletissue layers 316, 318, 315 each include one or more layers of SIStissue. Bioprosthetic device 310 further includes a synthetic portion314 including first mesh member 320 and second mesh member 322. It iswithin the scope of this disclosure to include any type of syntheticmesh member. For example, bioabsorbable and/or non-bioabsorbable meshmembers 320, 322 made of either woven or nonwoven PGA and/or PLAmixtures are included within the scope of disclosure of this invention.First mesh member 320 is coupled to and positioned to lie between toptissue layer 316 and middle tissue layer 315 and second mesh member 322is coupled to and positioned to lie between middle tissue layer 315 andbottom tissue layer 318, as shown in FIGS. 5 and 6. Each of the firstand second mesh members 320, 322 has a length, L, and a width, W,approximately equal to length, L, and width, W, of tissue layers 315,316, 318, of SIS portion 312. It is understood that in some embodiments,it may be preferable for the mesh to be slightly smaller than the SISportion.

In FIG. 5, second mesh member 322 is shown partially coated incomminuted SIS 340. Comminuted SIS may be used to fill the intersticesof second mesh member 322 to provide a stronger device. Other means forreinforcing bioprosthetic device 10 may be employed, including suturingor tacking the various layers together. Further, while comminuted SIS isdiscussed with respect to the embodiment shown in FIG. 5, it isunderstood that comminuted SIS may be used to coat the mesh or fibersfor any embodiment.

Another embodiment of the present invention includes a bioprostheticdevice 410 having a synthetic portion 414 including a mesh member 420,as shown in FIG. 7. Similar to the previously mentioned devices,bioprosthetic device 410 includes an SIS portion 412 having a top tissuelayer 416 and a bottom tissue layer 418 coupled to top tissue layer 416.Top and bottom tissue layers 416, 418 each include one or more layers ofSIS tissue. Mesh member 420 includes a central body portion (not shown)and outer wing portions 430, as shown in FIG. 7. Outer wing portions 430are extensions of the central body portion. Although four outer wingportions 430 are shown in FIG. 7, it is within the scope of thisdisclosure to include a mesh member having a body portion and any numberof wing portions 430 coupled to the body portion. The central bodyportion of mesh member 420 is formed to include a length and a widthequal to length, L, and width, W, of SIS portion 412. The central bodyportion is coupled to and positioned to lie between top tissue layer 416and bottom tissue layer 418 of SIS portion 420. Each wing portion 430 iscoupled to the central body portion of mesh member 420 and is positionedto extend beyond the length, L, and width, W, of SIS portion 412, asshown in FIG. 7. As mentioned before, outer wing portions 430 areextensions of the central body portion. Wing portions 430 provideadditional material for anchoring bioprosthetic device 410 to thesurrounding soft tissue. Because outer wing portions 430 extend beyondcentral body portion of mesh member 420, mesh member 420 has a lengthand a width greater than length, L, and width, W, of SIS portion 412.

Yet another embodiment of the present invention is shown in FIG. 8showing a bioprosthetic device 510 similar to bioprosthetic device 410,described above. Bioprosthetic device 510 includes an SIS portion 512and a synthetic portion 514 coupled to SIS portion 512. SIS portion 512includes a top tissue layer 516 which is circular in shape and a bottomtissue layer 518 which is also circular in shape. Each of the top andbottom tissue layers 516, 518 include one or more layers of SIS tissue.Top and bottom tissue layers 516, 518 each have a diameter, D1. Thesynthetic portion 514 of bioprosthetic device 510 includes a mesh member520 coupled to and positioned to lie between top and bottom tissuelayers 516, 518. Mesh member 520 is circular in shape and has adiameter, D2, which is greater than diameter, D1, of synthetic portion512. Therefore, as shown in FIG. 8, an outer rim portion 530 of meshmember 520 is provided. Similar to outer wing portions 430 ofbioprosthetic device 410, shown in FIG. 7, outer rim portion 530 ofbioprosthetic device 510 provides additional material for anchoringbioprosthetic device 510 to the surrounding soft tissue during surgery.

FIG. 9 shows a three-dimensional prosthetic device 610, having severalSIS layers 612, a synthetic reinforcing material 614 positioned to liebetween the SIS layers 612, and a three-dimensional synthetic portion624. The SIS layer 612 may comprise any number of tissue layers.Furthermore, illustratively, if more than one layer is used, the layersmay be laminated together. It is included within the scope of thisdisclosure to provide perforated tissue layers or any other physicalconfiguration of SIS. As with the embodiments shown in FIGS. 5-8, anynumber of SIS and reinforcing layers may be used, depending on theapplication.

Synthetic reinforcing material 614 illustratively comprises atwo-dimensional fibrous matrix construct, as shown in FIGS. 5-8, and mayhave the same length and width as the SIS layer, as shown in FIG. 5, maybe slightly smaller, or may extend beyond the ends of the SIS layer, asshown in FIGS. 7-8. Alternatively, synthetic reinforcing material maycomprise a three-dimensional mesh, textile, felt, or other fibrousnonwoven construct, which may be shaped or formed for the particularapplication. The fibers comprise any biocompatible material, includingPLA, PGA, PCL, PDO, TMC, PVA, or copolymers or blends thereof. In oneexample, mesh material is a 95:5 copolymer of PLA/PGA.

Three-dimensional synthetic portion 624 is a nonwoven material preparedto have numerous interconnecting pores or voids 626. Illustratively, thesize of the voids may range from 20 to 400 microns. However, the size ofthe voids may be adjusted depending on the application, and the size maybe manipulated by changing process steps during construction by alteringfreezing temperature, rate of temperature change and vacuum profile.Examples of various polymers that may be used for the foam, as well asvarious lyophilization profiles to control porosity, are described inU.S. Pat. Nos. 6,333,029 and 6,355,699, hereby incorporated byreference. Optionally, three-dimensional synthetic portion 624 furthercomprises a synthetic reinforcing layer 628 embedded within the foam.Reinforcing layer 628 illustratively provides enhanced mechanicalintegrity to the three-dimensional synthetic portion. In an illustratedembodiment, a Vicryl knitted mesh is used. However, other reinforcinglayers may be used.

Optionally, three-dimensional synthetic portion 624 may be a hybridECM/synthetic foam portion. In making such a foam, the polymer solutionis mixed with a slurry of comminuted SIS prior to lyophilization. SeeU.S. Application No. 60/388,761 entitled “Extracellular Matrix Scaffoldand Method for Making the Same” (Attorney Docket No. 265280-69963,DEP-702), hereby incorporated by reference.

FIG. 10 shows a bioprosthetic device 710 that is similar to that of FIG.9. In FIG. 10, the SIS layer 712 is sandwiched between twothree-dimensional synthetic portions 724, 730. Illustratively, boththree-dimensional synthetic portions are foams, having voids 726. Asshown, three-dimensional synthetic portion 724 has a reinforcing mesh728, while three-dimensional synthetic portion 730 does not have areinforcing member. However, other arrangements are possible, and FIG.11 shows an embodiment 810 where the SIS layer 812 is sandwiched betweentwo three-dimensional synthetic portions 824, 830, neither of which hasreinforcing members.

FIG. 12 shows another embodiment 910, wherein a single three-dimensionalsynthetic portion 964 is sandwiched between two SIS layers 952, 953. Asshown, three-dimensional synthetic portion 964 is a foam, with voids966, but other three-dimensional synthetic portions may be used.

FIG. 13 shows a woven mesh 912 made from strips 928 of SIS. Fresh,lyophilized, or laminated strips of SIS may be cut into narrower stripsand woven into a mesh. The strips may be of any width, depending on theapplication, for example 0.1 to 20 mm, more particularly 1.0 mm widestrips. Optionally, the woven strips may be laminated together toprovide enhanced mechanical support. The SIS woven mesh may be used asthe SIS layer in any of the above embodiments. When used with thesynthetic foams, if sufficient space is provided in the weaving, thefoams will form through the spaces within the mesh.

Reinforced SIS devices may also be fabricated using other processes. Forexample, a synthetic polymer mesh coated with comminuted SIS (or otherECM) may be sandwiched in the middle of twenty strips of SIS (10 layerson each side), laminated under high pressure, and subsequently driedunder vacuum pressure in a flat-bed gel drier system. The comminuted SIS(or other comminuted ECM) may be prepared in the manner described inU.S. patent application Publication No. 20030044444 A1 entitled “PorousExtracellular Matrix Scaffold and Method” by P. Malaviya et al., theentirety of which is hereby incorporated by reference.

Such a laminated and dried implant is significantly more resistant todelamination (175 minutes to delaminate using a water bath delaminationprotocol described below) as compared to implants made either with highpressure lamination but without the comminuted SIS coating (60 minutesto delaminate) or with the comminuted SIS coating but without the highpressure lamination (20-30 minutes to delaminate). It is believed thatcoating the synthetic mesh with comminuted SIS and then initiatinglamination under high pressure has a synergistic effect on theresistance to delamination.

Such relatively high, positive pressure may be applied in a number ofdifferent manners. In an exemplary implementation, the relatively high,positive pressure is applied by use of a pneumatic cylinder pressassembly. Other positive pressure sources may also be used. Moreover,the pressure may be applied in a wide range of magnitudes.

Implants fabricated in such a manner may have higher, and perhapssignificantly higher, mechanical properties. In specific exemplary uses,such implants may be used where diseased/damaged tissue needs to beregenerated under high load conditions. For example, such implants maybe used for the augmentation of damaged/resected hip capsule followingprimary or revision hip surgery, for patellar tendon regeneration, forthe repair of large rotator cuff tears, for spinal ligamentregeneration, and the like.

Other methods for fabricating reinforced SIS implants are alsocontemplated. For example, the surface of the synthetic polymer ischaracteristically hydrophobic in nature, while the SIS surface ishydrophilic. The surface of the synthetic polymer component may bemodified to render it more hydrophilic, and, as a result, morecompatible with the SIS surface. The more hydrophilic polymer surfacecreates a like-like attraction (e.g., weak force and hydrogen bonding)between the synthetic polymer component and the SIS thereby reducing theoccurrences of delamination of the device. Such modification of thesurface of the polymer component may also be used in conjunction withconcepts described above for fabricating a pressure-laminated andvacuum-dehydrated composite.

Surface modification of the synthetic polymer component, such as aresorbable polyester, may be accomplished by numerous techniques suchas, for example, traditional wet chemistry or gas plasma processing.Traditional chemistries may include surface hydrolysis and amidationtechniques. Base or acid catalyzed hydrolysis of the synthetic polymer(e.g., polyester) creates pendant hydroxyl and carboxylic acid moieties,while treatment with a bifunctional amine affords free aminefunctionalities coupled to the surface. It should be appreciated thatsuch a bifunctional amine may have an amine on both ends thereof, or,alternatively, may have an amine on one end with any type of hydrophilicgroup on the other end.

Gas plasma treatment of the synthetic polymer generates high energyreactive species that bond to surfaces. For example, treatment of apolymer surface with ammonia plasma generates an amine functionalizedsurface. Similarly, an oxidative plasma may be produced by filteringaqueous hydrogen peroxide into the plasma chamber at approximately 400mTorr and applying an approximately 200 Watt radio frequency forapproximately 3, 5, or 10 minutes.

It should be appreciated that such treatment of the synthetic polymermay also be used to functionalize non-absorbable polymers.

By taking these approaches to strengthen SIS laminates, crosslinking ofthe SIS material may be avoided, thus retaining more of its biochemicaland biological properties. However, to fit the needs of a given implantdesign, crosslinking of the SIS material may be used in conjunction withthe herein described strengthening techniques.

The composite implants described herein may be used where diseased ordamaged tissue needs to be regenerated under high load conditions, forexample, for the augmentation of damaged/resected hip capsule followingprimary or revision hip surgery, for patellar or Achilles tendonregeneration, for the repair of large rotator cuff tears, for spinalligament regeneration, etcetera.

It should be appreciated that devices may be fabricated which include acombination of both surface treatment and coating of the syntheticpolymer component. For example, the synthetic polymer component mayfirst be treated to enhance the hydrophilicity of it surface (e.g., byuse of wet chemistry or gas plasma treatment). Once treated, thesynthetic polymer component may be coated in comminuted SIS (or othernaturally occurring extracellular matrix material) in the mannerdescribed above. Thereafter, the synthetic polymer component may besecured to layers of SIS (or other ECM). For example, the treated andcoated synthetic polymer layer may be laminated to one or more SISlayers under high pressure and subsequently dried under vacuum pressurein the manner described above.

While the devices shown in FIGS. 9-13 specific embodiments, it isunderstood that other arrangements are within the scope of thisinvention. For example, in FIGS. 10-11, an SIS layer is sandwichedbetween two three-dimensional foam sections, with or without areinforcing material embedded within the foam. Additional reinforcinglayers, as shown in FIG. 9 may be used with these embodiments.Similarly, when a single three-dimensional foam portion is sandwichedbetween two SIS layers, as in FIG. 12, a layer of reinforcing materialmay be used, depending upon the application. In still anotherembodiment, the reinforcing portion may comprise a three-dimensionalmesh or textile, and the three-dimensional foam portion may be omitted.It is also within the scope of this disclosure to further define the SISportion to include sheets, perforated sheets, or any other physicalconfiguration of SIS. Furthermore, the synthetic portion may compriseProlene™ (Ethicon, Inc, Somerville, N.J.) meshes and/or sutures, Vicryl™(Ethicon, Inc, Somerville, N.J.) meshes and/or sutures, Mersilene™(Ethicon, Inc, Somerville, N.J.) meshes, PDS II™ (Ethicon, Inc.,Somerville, N.J.) meshes or sutures, Panacryl™ (Ethicon, Inc.,Somerville, N.J.) meshes or sutures, and Monocryl™ meshes or sutures,for example. Additional two or three-dimensional meshes may beconstructed for particular applications. Further it is within the scopeof this disclosure to include bioprosthetic devices where the SISportion includes any number of tissue layers and where multiple tissuelayers are positioned to lie along each synthetic layer. The SIS layersmay be dehydrated prior to or subsequent to assembly of the device.Further, any shape and/or orientation of the SIS portion and thesynthetic portion of the bioprosthetic device is within the scope ofthis disclosure; FIGS. 1-13 are merely examples of various embodimentsof the present invention.

EXAMPLE 1

Sheets of clean, disinfected porcine SIS material were obtained asdescribed in U.S. Pat. Nos. 4,902,508 and 4,956,178. Ten strips, 3.5inches wide and 6 inches long were cut. The strips were hydrated byplacing in RO water, at room temperature, for 5 minutes.

To assemble the implant, five SIS strips were placed on top of eachother, while ensuring no air bubbles were trapped between the strips. Aknitted Panacryl™ mesh, 2 inches wide and 5 inches long, was placedcentrally on the 5-layer thick SIS strip. The mesh had been pretreatedto remove any traces of oil or other contaminants due to handling. Thiswas done by a series of rinses, each 2 minutes long, in 100%, 90%, 80%,70% ethanol (200 proof) in RO water, followed by a final 5 minute in ROwater. Subsequently, a second 5-layer thick strip of SIS was assembledand placed to sandwich the mesh between the two SIS strips.

The implant was dried under vacuum pressure using a gel drier system(Model FB-GD-45, Fisher Scientific, Pittsburgh, Pa.) for 3 hours. Thegel drier bed temperature was set at 30° C. for the procedure. Thisdrying procedure results in “squeezing out” of the bulk water in theimplant and also reduces the amount of bound water within the tissue,resulting in a final moisture of between 7%-8%. This process alsoresults in a physical crosslinking between the laminates of SIS andbetween the mesh and adjacent SIS laminates.

Non-reinforced SIS strips were made in the same way as described, exceptthat no mesh material was placed between the strips of SIS.

EXAMPLE 2

This example describes the preparation of three-dimensional compositetissue implants incorporating a biodegradable SIS laminated sheet, asynthetic reinforcement in the form of a biodegradable mesh, and asynthetic degradable foam.

A solution of the polymer to be lyophilized to form the foam componentwas prepared in a four step process. A 95:5 weight ratio solution of1,4-dioxane/(40/60 PCL/PLA) was made and poured into a flask. The flaskwas placed in a water bath, stirring at 60-70° C. for 5 hrs. Thesolution was filtered using an extraction thimble, extra coarseporosity, type ASTM 170-220 (EC) and stored in flasks.

A three-dimensional mesh material composed of a 95:5 copolymer ofpolylactic/polyglycolic acid (PLA/PGA) knitted mesh was rendered flat tocontrol curling by using a compression molder at 80° C. for 2 min. Afterpreparing the mesh, 0.8-mm metal shims were placed at each end of a 4×4inch aluminum mold, and the mesh was sized to fit the mold. Thesynthetic mesh was then laid into the mold, covering both shims. Next,an SIS laminated sheet was placed over the mesh followed by additionalshims to cover the edges of the SIS and synthetic mesh.

The polymer solution (40:60 PCL/PLA) was added into mold such that thesolution covered the sheet of SIS as well as the mesh and reached alevel of 3.0 mm in the mold.

The mold assembly then was placed on the shelf of the lyophilizer(Virtis, Gardiner, N.Y.) and the freeze dry sequence begun. The freezedry sequence used in this example was: 1) −17° C. for 60 minutes; 2) −5°C. for 60 minutes under vacuum of 100 mT; 3) 5° C. for 60 minutes undervacuum of 20 mT; 4) 20° C. for 60 minutes under vacuum of 20 mT.

After the cycle was completed, the mold assembly was taken out of thefreeze drier and allowed to degas in a vacuum hood for 2 to 3 hours, andstored under nitrogen.

The resultant bioprosthetic device has a structure as illustrated inFIG. 9. The three-dimensional mesh provides both mechanical strength andthree-dimensional structure to the resultant device. The foam may beshaped or sculpted for the particular application, and the mesh/SISlayers may be trimmed to fit. It is also understood that the mold couldbe provided in the desired shape, reducing or obviating the need forsculpting or trimming.

EXAMPLE 3

This example uses the process outlined in Example 2 to fabricate abiodegradable composite scaffold of the present invention where the foamcomponent is a 65:35 PGA/PCL copolymer.

EXAMPLE 4

This example uses the process outlined in Example 2 to fabricate abiodegradable composite scaffold of the present invention where thesynthetic knitted mesh component is composed of 100% PDO.

EXAMPLE 5

This example uses the process outlined in Example 2 to fabricate abiodegradable composite scaffold of the present invention where in placeof a three-dimensional mesh, the synthetic component is a nonwovenfibrous structure composed of either 100% PDO, 100% 90/10 PGA/PLA or acombination of the two.

EXAMPLE 6

This example uses the process outlined in Example 2 to fabricate abiodegradable composite scaffold of the present invention where the SIScomponent is soaked overnight in the polymer solution (5% wt 60/40PLA/PCL in dioxane) prior to placement over the synthetic mesh. Enhancedlamination between the components was found when this additional soakingstep was added to the process as evidenced by a composite with a greaterdegree of handlability.

EXAMPLE 7

This example uses the process outlined in Example 2 to fabricate abiodegradable composite scaffold of the present invention where the SIScomponent is a single layer sheet rather than a laminated sheet.

EXAMPLE 8

This example uses the process outlined in Example 2 to fabricate abiodegradable composite scaffold of the present invention where the SISlaminated sheet is perforated with holes ranging from 1 mm-1 cm. Theseperforations allow for enhanced penetration of the polymer solutionthrough the SIS sheet.

EXAMPLE 9

This example uses the process outlined in Example 2 to fabricate abiodegradable composite scaffold of the present invention where the SISreinforcing component is a “woven mesh” of laminated strips sandwichedbetween two layers of 60/40 PLA/PCL foam. FIG. 13 shows such a wovenmesh. FIG. 11, wherein the SIS layer is a woven mesh of FIG. 13,illustrates the construct of this Example.

EXAMPLE 10

A soaking test was performed to test resistance to delamination.Implants made as specified in Example 1 (both reinforced andnon-reinforced) were cut into several strips 1 cm wide by 5 cm long,using a #10 scalpel blade. The strips were immersed in RO water, at roomtemperature for 1, 2, 5, 10, 20, 30, or 60 minutes. Delamination wasdetected at the edges of the implants by direct visual observation. Allimplants showed obvious signs of delamination at 1 hour. Innon-reinforced implants, delamination was first visually observedbetween 40-60 minutes, whereas in the reinforced samples delaminationwas apparent between 20-30 minutes.

EXAMPLE 11

This example illustrates the enhanced mechanical properties of aconstruct reinforced with absorbable mesh. Preparation ofthree-dimensional elastomeric tissue implants with and without areinforcement in the form of a biodegradable mesh are described. While afoam is used for the elastomeric tissue in this example, it is expectedthat similar results will be achieved with an ECM and a biodegradablemesh.

A solution of the polymer to be lyophilized to form the foam componentwas prepared in a four step process. A 95/5 weight ratio solution of1,4-dioxane/(40/60 PCL/PLA) was made and poured into a flask. The flaskwas placed in a water bath, stirring at 70° C. for 5 hrs. The solutionwas filtered using an extraction thimble, extra coarse porosity, typeASTM 170-220 (EC) and stored in flasks.

Reinforcing mesh materials formed of a 90/10 copolymer ofpolyglycolic/polylactic acid (PGA/PLA) knitted (Code VKM-M) and woven(Code VWM-M), both sold under the tradename VICRYL were rendered flat byironing, using a compression molder at 80° C./2 min. After preparing themeshes, 0.8-mm shims were placed at each end of a 15.3×15.3 cm aluminummold, and the mesh was sized (14.2 mm) to fit the mold. The mesh wasthen laid into the mold, covering both shims. A clamping block was thenplaced on the top of the mesh and the shim such that the block wasclamped properly to ensure that the mesh had a uniform height in themold. Another clamping block was then placed at the other end, slightlystretching the mesh to keep it even and flat.

As the polymer solution was added to the mold, the mold was tilted toabout a 5 degree angle so that one of the non-clamping sides was higherthan the other. Approximately 60 ml of the polymer solution was slowlytransferred into the mold, ensuring that the solution was well dispersedin the mold. The mold was then placed on a shelf in a Virtis (Gardiner,N.Y.), Freeze Mobile G freeze dryer. The following freeze dryingsequence was used: 1) 20° C. for 15 minutes; 2) −5° C. for 120 minutes;3) −5° C. for 90 minutes under vacuum 100 milliTorr; 4) 5° C. for 90minutes under vacuum 100 milliTorr; 5) 20° C. for 90 minutes undervacuum 100 milliTorr. The mold assembly was then removed from thefreezer and placed in a nitrogen box overnight. Following the completionof this process the resulting implant was carefully peeled out of themold in the form of a foam/mesh sheet.

Nonreinforced foams were also fabricated. To obtain non-reinforcedfoams, however, the steps regarding the insertion of the mesh into themold were not performed. The lyophilization steps above were followed.

EXAMPLE 12

Lyophilized 40/60 polycaprolactone/polylactic acid, (PCL/PLA) foam, aswell as the same foam reinforced with an embedded VICRYL knitted mesh,were fabricated as described in Example 3. These reinforced implantswere tested for suture pull-out strength and compared to non-reinforcedfoam prepared following the procedure of Example 11.

For the suture pull-out strength test, the dimensions of the specimenswere approximately 5 cm×9 cm. Specimens were tested for pull-outstrength in the wale direction of the mesh (knitting machine axis). Asize 0 polypropylene monofilament suture (Code 8834H), sold under thetradename PROLENE (by Ethicon, Inc., Somerville, N.J.) was passedthrough the mesh 6.25 mm from the edge of the specimens. The ends of thesuture were clamped into the upper jaw and the mesh or the reinforcedfoam was clamped into the lower jaw of an Instron model 4501 (Canton,Mass.). The Instron machine, with a 20 lb load cell, was activated usinga cross-head speed of 2.54 cm per minute. The ends of the suture werepulled at a constant rate until failure occurred. The peak load (lbs.)experienced during the pulling was recorded.

The results of this test are shown below in Table 1. TABLE 1 SuturePull-Out Data (lbs.) Time Foam Mesh Foamed Mesh 0 Day 0.46 5.3 +/− 0.85.7 +/− 0.3 7 Day* — 4.0 +/− 1.0 5.0 +/− 0.5*exposed for 7 days to phosphate buffered saline at 37° C. in atemperature controlled water bath.

These data show that a reinforced foam has improved pull-out strengthverses either foam or mesh alone.

EXAMPLE 13

Sheets of clean, disinfected porcine SIS material were obtained asdescribed in patents U.S. Pat. No. 4,902,508 and U.S. Pat. No.4,956,178. Twenty strips, 3.5 inches wide and 6 inches long were cut.The strips were hydrated by placing in RO water, at room temperature,for 5 minutes.

To assemble the implant, ten SIS strips were placed longitudinally ontop of each other, while ensuring no air bubbles were trapped betweenthe strips. A knitted Panacryl™ mesh, 2 inches wide and 5 inches long,was immersed in a comminuted SIS suspension (disclosed in U.S. patentpublication 2003004444 A1) (approximately 1% solids w/v). This resultsin a near-uniform coating of the synthetic mesh with the wet fibers ofthe SIS suspension such that the SIS fibers are intertwined andinterlocked with the porous knitted mesh. The coated mesh was placedcentrally on the 10-layer thick SIS strip. Subsequently, a second10-layer thick strip of SIS was assembled and placed to sandwich thecoated mesh between the two SIS strips.

Lamination of the thus assembled implant was initiated under highpressure using a pneumatic cylinder press (Model BTP-501-A, TRDManufacturing Inc., Loves Park, Ill. 61111.) The press was operated at40 psi air pressure to drive the piston, which resulted in a totalcompressive force of approximately 4000 lbs on the assembled implant.This force created an approximate average lamination pressure of 180 psion the implant. The sample was compressed for 15 minutes at roomtemperature. This process resulted in a “squeezing out” of most of thebulk water associated with the SIS laminates and comminuted SIS andcreated a partially wet laminated implant.

The implant was subsequently dried under vacuum pressure using aflat-bed gel drier system (Model FB-GD-45, Fisher Scientific,Pittsburgh, Pa.) for 3 hours. The gel drier bed temperature was set at30° C. for the procedure. This drying procedure resulted in a furtherreduction of the bulk water associated with the implant and also reducedthe amount of bound water within the implant, resulting in a finalmoisture content between 7%-8%. This process also results in a physicalcrosslinking between the laminates of SIS and the comminuted SIS coatingthe synthetic mesh by further increasing the surface contact area of SISmaterial.

Implants were also made as described above but without coating thePanacryl™ mesh with the comminuted SIS fibers.

EXAMPLE 14

An agitation test was performed to test for resistance to delamination.High-pressure laminated implants made as described in Example 13 (bothwith and without SIS coating on the mesh) were cut into several strips 1cm wide and 5 cm long. Each strip was placed in 20 mL of reverse osmosiswater at room temperature in a 50 mL glass flask. The flasks weresecured on a shaker table set to agitate the samples at 300 rpm. Everyfive minutes the strips were examined for delamination between the SISlaminates and the synthetic mesh. On average, reinforced implantswithout the comminuted SIS-coated mesh delaminated after 60 minutes ofagitation, whereas, reinforced implants with the comminuted SIS-coatingdelaminated after 175 minutes.

It is expected that high pressure laminated SIS implants reinforced witha comminuted SIS coated synthetic mesh will also have higher (andperhaps significantly higher) mechanical properties (e.g. higher ballburst strength) as compared with implants made without high pressurelamination or without a comminuted SIS coating on the synthetic mesh.

Although the invention has been described in detail with reference tocertain preferred embodiments, variations and modifications exist withinthe scope and spirit of the invention as described and defined in thefollowing claims.

1. A method of making a bioprosthetic device, the method comprising thesteps of: coating a synthetic layer with a comminuted naturallyoccurring extracellular matrix material, positioning the coatedsynthetic layer between a first layer of naturally occurringextracellular matrix material and a second layer of naturally occurringextracellular matrix material to make an assembly, and applying positivepressure to the assembly.
 2. The method of claim 1, wherein the applyingstep comprises pressing the assembly together.
 3. The method of claim 1,wherein the applying step comprises pressing the assembly with apneumatic press.
 4. The method of claim 1, wherein the applying stepcomprises: positioning the assembly in a press, and operating the pressto exert pressure on assembly.
 5. The method of claim 1, furthercomprising the step of drying the assembly after the applying step. 6.The method of claim 5, wherein the drying step comprises drying theassembly under vacuum pressure.
 7. The method of claim 1, wherein boththe first and second naturally occurring extracellular matrix materiallayers comprise an SIS layer.
 8. The method of claim 7, wherein the SISlayer comprises a plurality of SIS strips laminated together.
 9. Themethod of claim 7, wherein the SIS layer comprises a woven mesh ofstrips of SIS.
 10. The method of claim 1, wherein the synthetic layercomprises a fibrous material.
 11. The method of claim 10, wherein thefibrous material is selected from the group consisting of mesh, textile,and felt.
 12. The method of claim 10, wherein the fibrous material is abioabsorbable material selected from the group consisting of PLA, PGA,PCL, PDO, TMC, PVA, copolymers thereof, and blends thereof.
 13. Themethod of claim 1, wherein the coating step comprises immersing thesynthetic layer in a suspension of comminuted naturally occurringextracellular matrix material.
 14. A method of making a bioprostheticdevice, the method comprising the steps of: coating a synthetic layerwith comminuted naturally occurring extracellular matrix material,positioning the coated synthetic layer between a first layer ofnaturally occurring extracellular matrix material and a second layer ofnaturally occurring extracellular matrix material to make an assembly,and operating a press to exert positive pressure on the assembly. 15.The method of claim 14, wherein the operating step comprises operating apneumatic press to exert positive pressure on the assembly.
 16. Themethod of claim 14, further comprising the step of drying the assemblyafter the operating step.
 17. The method of claim 16, wherein the dryingstep comprises drying the assembly under vacuum pressure.
 18. The methodof claim 14, wherein both the first and second naturally occurringextracellular matrix material layers comprise an SIS layer.
 19. Themethod of claim 18, wherein the SIS layer comprises a plurality of SISstrips laminated together.
 20. The method of claim 14, wherein the SISlayer comprises a woven mesh of strips of SIS.
 21. The method of claim14, wherein the synthetic layer comprises a fibrous material.
 22. Themethod of claim 21, wherein the fibrous material is selected from thegroup consisting of mesh, textile, and felt.
 23. The method of claim 21,wherein the fibrous material is a bioabsorbable material selected fromthe group consisting of PLA, PGA, PCL, PDO, TMC, PVA, copolymersthereof, and blends thereof.
 24. A bioprosthetic device made accordingto claim
 1. 25. A bioprosthetic device made according to claim 14.